1. SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis
- Author
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Chao Qin, Youliang Rao, Hao Yuan, Ting-Yu Wang, Jun Zhao, Bianca Espinosa, Yongzhen Liu, Shu Zhang, Ali Can Savas, Qizhi Liu, Mehrnaz Zarinfar, Stephanie Rice, Jill Henley, Lucio Comai, Nicholas A. Graham, Casey Chen, Chao Zhang, and Pinghui Feng
- Subjects
Inflammation ,Multidisciplinary ,SARS-CoV-2 ,Transcription Factor RelA ,RNA-Binding Proteins ,Viral Nonstructural Proteins ,Virus Replication ,Antiviral Agents ,COVID-19 Drug Treatment ,Enzyme Activation ,Mice ,Pyrimidines ,Aspartate Carbamoyltransferase ,Animals ,Humans ,Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) ,Enzyme Inhibitors ,Dihydroorotase - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
- Published
- 2022